Pulmonary function and atherosclerosis in the general population: causal associations and clinical implications.

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.

High prevalence of interstitial lung abnormalities in middle-aged never-smokers.

Background: Interstitial lung abnormalities (ILA) are incidental findings on chest computed tomography (CT). These patterns can present at an early stage of fibrotic lung disease. Our aim was to estimate the prevalence of ILA in the Swedish population, in particular in never-smokers, and find out its association with demographics, comorbidities and symptoms. Methods: Participants were recruited to the Swedish CArdioPulmonary BioImage Study (SCAPIS), a population-based survey including men and women aged 50-64 years performed at six university hospitals in Sweden. CT scan, spirometry and questionnaires were performed. ILA were defined as cysts, ground-glass opacities, reticular abnormality, bronchiectasis and honeycombing. Findings: Out of 29 521 participants, 14 487 were never-smokers and 14 380 were men. In the whole population, 2870 (9.7%) had ILA of which 134 (0.5%) were fibrotic. In never-smokers, the prevalence was 7.9% of which 0.3% were fibrotic. In the whole population, age, smoking history, chronic bronchitis, cancer, coronary artery calcium score and high-sensitive C-reactive protein were associated with ILA. Both ILA and fibrotic ILA were associated with restrictive spirometric pattern and impaired diffusing capacity of the lung for carbon monoxide. However, individuals with ILA did not report more symptoms compared with individuals without ILA. Interpretation: ILA are common in a middle-aged Swedish population including never-smokers. ILA may be at risk of being underdiagnosed among never-smokers since they are not a target for screening.

Consequences of Using Post- or Prebronchodilator Reference Values in Interpreting Spirometry.

Rationale: Postbronchodilator spirometry is used for the diagnosis of chronic obstructive pulmonary disease. However, prebronchodilator reference values are used for spirometry interpretation. Objectives: To compare the resulting prevalence rates of abnormal spirometry and study the consequences of using pre- or postbronchodilator reference values generated within SCAPIS (Swedish CArdioPulmonary bioImage Study) when interpreting postbronchodilator spirometry in a general population. Methods: SCAPIS reference values for postbronchodilator and prebronchodilator spirometry were based on 10,156 and 1,498 never-smoking, healthy participants, respectively. We studied the associations of abnormal spirometry, defined by using pre- or postbronchodilator reference values, with respiratory burden in the SCAPIS general population (28,851 individuals). Measurements and Main Results: Bronchodilation resulted in higher predicted medians and lower limits of normal (LLNs) for FEV1/FVC ratios. The prevalence of postbronchodilator FEV1/FVC ratio lower than the prebronchodilator LLN was 4.8%, and that of postbronchodilator FEV1/FVC lower than the postbronchodilator LLN was 9.9%, for the general population. An additional 5.1% were identified as having an abnormal postbronchodilator FEV1/FVC ratio, and this group had more respiratory symptoms, emphysema (13.5% vs. 4.1%; P < 0.001), and self-reported physician-diagnosed chronic obstructive pulmonary disease (2.8% vs. 0.5%, P < 0.001) than subjects with a postbronchodilator FEV1/FVC ratio greater than the LLN for both pre- and postbronchodilation. Conclusions: Pre- and postbronchodilator spirometry reference values differ with regard to FEV1/FVC ratio. Use of postbronchodilator reference values doubled the population prevalence of airflow obstruction; this was related to a higher respiratory burden. Using postbronchodilator reference values when interpreting postbronchodilator spirometry might enable the identification of individuals with mild disease and be clinically relevant.

Consensus clustering with missing labels (ccml): a consensus clustering tool for multi-omics integrative prediction in cohorts with unequal sample coverage.

Multi-omics data integration is a complex and challenging task in biomedical research. Consensus clustering, also known as meta-clustering or cluster ensembles, has become an increasingly popular downstream tool for phenotyping and endotyping using multiple omics and clinical data. However, current consensus clustering methods typically rely on ensembling clustering outputs with similar sample coverages (mathematical replicates), which may not reflect real-world data with varying sample coverages (biological replicates). To address this issue, we propose a new consensus clustering with missing labels (ccml) strategy termed ccml, an R protocol for two-step consensus clustering that can handle unequal missing labels (i.e. multiple predictive labels with different sample coverages). Initially, the regular consensus weights are adjusted (normalized) by sample coverage, then a regular consensus clustering is performed to predict the optimal final cluster. We applied the ccml method to predict molecularly distinct groups based on 9-omics integration in the Karolinska COSMIC cohort, which investigates chronic obstructive pulmonary disease, and 24-omics handprint integrative subgrouping of adult asthma patients of the U-BIOPRED cohort. We propose ccml as a downstream toolkit for multi-omics integration analysis algorithms such as Similarity Network Fusion and robust clustering of clinical data to overcome the limitations posed by missing data, which is inevitable in human cohorts consisting of multiple data modalities. The ccml tool is available in the R language (https://CRAN.R-project.org/package=ccml, https://github.com/pulmonomics-lab/ccml, or https://github.com/ZhoulabCPH/ccml).

miRNA-mRNA-protein dysregulated network in COPD in women.

Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease caused by a multitude of underlying mechanisms, and molecular mechanistic modeling of COPD, especially at a multi-molecular level, is needed to facilitate the development of molecular diagnostic and prognostic tools and efficacious treatments. Objectives: To investigate the miRNA-mRNA-protein dysregulated network to facilitate prediction of biomarkers and disease subnetwork in COPD in women. Measurements and Results: Three omics data blocks (mRNA, miRNA, and protein) collected from BAL cells from female current-smoker COPD patients, smokers with normal lung function, and healthy never-smokers were integrated with miRNA-mRNA-protein regulatory networks to construct a COPD-specific dysregulated network. Furthermore, downstream network topology, literature annotation, and functional enrichment analysis identified both known and novel disease-related biomarkers and pathways. Both abnormal regulations in miRNA-induced mRNA transcription and protein translation repression play roles in COPD. Finally, the let-7-AIFM1-FKBP1A pathway is highlighted in COPD pathology. Conclusion: For the first time, a comprehensive miRNA-mRNA-protein dysregulated network of primary immune cells from the lung related to COPD in females was constructed to elucidate specific biomarkers and disease pathways. The multi-omics network provides a new molecular insight from a multi-molecular aspect and highlights dysregulated interactions. The highlighted let-7-AIFM1-FKBP1A pathway also indicates new hypotheses of COPD pathology.

Increased cytotoxic T-cells in the airways of adults with former bronchopulmonary dysplasia.

RATIONALE: Bronchopulmonary dysplasia (BPD) in preterm-born infants is a risk factor for chronic airway obstruction in adulthood. Cytotoxic T-cells are implicated in COPD, but their involvement in BPD is not known. OBJECTIVES: To characterise the distribution of airway T-cell subsets in adults with a history of BPD. METHODS: Young adults with former BPD (n=22; median age 19.6 years), age-matched adults born preterm (n=22), patients with allergic asthma born at term (n=22) and healthy control subjects born at term (n=24) underwent bronchoalveolar lavage (BAL). T-cell subsets in BAL were analysed using flow cytometry. RESULTS: The total number of cells and the differential cell counts in BAL were similar among the study groups. The percentage of CD3+CD8+ T-cells was higher (p=0.005) and the proportion of CD3+CD4+ T-cells was reduced (p=0.01) in the BPD group, resulting in a lower CD4/CD8 ratio (p=0.007) compared to the healthy controls (median 2.2 versus 5.3). In BPD and preterm-born study subjects, both CD3+CD4+ T-cells (rs=0.38, p=0.03) and CD4/CD8 ratio (rs=0.44, p=0.01) correlated positively with forced expiratory volume in 1 s (FEV1). Furthermore, CD3+CD8+ T-cells were negatively correlated with both FEV1 and FEV1/forced vital capacity (rs= -0.44, p=0.09 and rs= -0.41, p=0.01, respectively). CONCLUSIONS: Young adults with former BPD have a T-cell subset pattern in the airways resembling features of COPD. Our findings are compatible with the hypothesis that CD3+CD8+ T-cells are involved in mechanisms behind chronic airway obstruction in these patients.

Association of cardiometabolic risk factors with hospitalisation or death due to COVID-19: population-based cohort study in Sweden (SCAPIS).

OBJECTIVE: To assess the association of cardiometabolic risk factors with hospitalisation or death due to COVID-19 in the general population. DESIGN, SETTING AND PARTICIPANTS: Swedish population-based cohort including 29 955 participants. EXPOSURES: Cardiometabolic risk factors assessed between 2014 and 2018. MAIN OUTCOME MEASURES: Hospitalisation or death due to COVID-19, as registered in nationwide registers from 31 January 2020 through 12 September 2020. Associations of cardiometabolic risk factors with the outcome were assessed using logistic regression adjusted for age, sex, birthplace and education. RESULTS: Mean (SD) age was 61.2 (4.5) and 51.5% were women. 69 participants experienced hospitalisation or death due to COVID-19. Examples of statistically significant associations between baseline factors and subsequent hospitalisation or death due to COVID-19 included overweight (adjusted OR (aOR) vs normal weight 2.73 (95% CI 1.25 to 5.94)), obesity (aOR vs normal weight 4.09 (95% CI 1.82 to 9.18)), pre-diabetes (aOR vs normoglycaemia 2.56 (95% CI 1.44 to 4.55)), diabetes (aOR vs normoglycaemia 3.96 (95% CI 2.13 to 7.36)), sedentary time (aOR per hour/day increase 1.10 (95% CI 1.02 to 1.17)), grade 2 hypertension (aOR vs normotension 2.44 (95% CI 1.10 to 5.44)) and high density lipoprotein cholesterol (aOR per mmol/L increase 0.33 (95% CI 0.17 to 0.65)). Statistically significant associations were not observed for grade 1 hypertension (aOR vs normotension 1.03 (95% CI 0.55 to 1.96)), current smoking (aOR 0.56 (95% CI 0.24 to 1.30)), total cholesterol (aOR per mmol/L increase 0.90 (95% CI 0.71 to 1.13)), low density lipoprotein cholesterol (aOR per mmol/L increase 0.90 (95% CI 0.69 to 1.15)) and coronary artery calcium score (aOR per 10 units increase 1.00 (95% CI 0.99 to 1.01)). CONCLUSIONS: In a large population-based sample from the general population, several cardiometabolic risk factors were associated with hospitalisation or death due to COVID-19.

Outcomes of patients with advanced idiopathic pulmonary fibrosis treated with nintedanib or pirfenidone in a real-world multicentre cohort.

BACKGROUND AND OBJECTIVE: Antifibrotic therapy with nintedanib or pirfenidone slows disease progression and reduces mortality in patients with idiopathic pulmonary fibrosis (IPF). However, patients with advanced IPF, as defined by forced vital capacity (FVC) < 50% and/or diffusion capacity for carbon monoxide (DLCO) < 30% of predicted, have not been included in randomized trials, and the outcomes of such patients who initiate treatment are not well understood. We determined lung function, disease progression and mortality outcomes following initiation of antifibrotic therapy in patients with advanced IPF at the time of treatment initiation compared to those with mild-moderate IPF. METHODS: We included 502 patients enrolled in IPF registries from four Nordic countries. Linear mixed models were used to assess change in FVC and DLCO over time. Cox proportional hazards models were used to assess transplant-free survival and progression- and transplant-free survival. RESULTS: Of 502 patients, 66 (13%) had advanced IPF. Annual change in FVC was -125 ml (95% CI -163, -87) among patients with mild-moderate IPF, and +28 ml (95% CI -96, +152) among those with advanced IPF. Advanced IPF at treatment initiation was associated with poorer transplant-free survival (hazard ratio [HR] 2.39 [95% CI 1.66, 3.43]) and progression- and transplant-free survival (HR 1.60 [95% CI 1.15, 2.23]). CONCLUSION: In a broadly representative IPF population, patients with advanced IPF at the initiation of antifibrotic therapy did not have greater lung function decline over time compared with those with mild-moderate IPF, but had substantially higher mortality. Prospective studies are needed to determine the effect of antifibrotic therapy in patients with advanced IPF.

High-Precision Automated Workflow for Urinary Untargeted Metabolomic Epidemiology.

Urine is a noninvasive biofluid that is rich in polar metabolites and well suited for metabolomic epidemiology. However, because of individual variability in health and hydration status, the physiological concentration of urine can differ >15-fold, which can pose major challenges in untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics. Although numerous urine normalization methods have been implemented (e.g., creatinine, specific gravity-SG), most are manual and, therefore, not practical for population-based studies. To address this issue, we developed a method to measure SG in 96-well-plates using a refractive index detector (RID), which exhibited accuracy within 85-115% and <3.4% precision. Bland-Altman statistics showed a mean deviation of -0.0001 SG units (limits of agreement: -0.0014 to 0.0011) relative to a hand-held refractometer. Using this RID-based SG normalization, we developed an automated LC-MS workflow for untargeted urinary metabolomics in a 96-well-plate format. The workflow uses positive and negative ionization HILIC chromatography and acquires mass spectra in data-independent acquisition (DIA) mode at three collision energies. Five technical internal standards (tISs) were used to monitor data quality in each method, all of which demonstrated raw coefficients of variation (CVs) < 10% in the quality controls (QCs) and < 20% in the samples for a small cohort (n = 87 urine samples, n = 22 QCs). Application in a large cohort (n = 842 urine samples, n = 248 QCs) demonstrated CVQC < 5% and CVsamples < 16% for 4/5 tISs after signal drift correction by cubic spline regression. The workflow identified >540 urinary metabolites including endogenous and exogenous compounds. This platform is suitable for performing urinary untargeted metabolomic epidemiology and will be useful for applications in population-based molecular phenotyping.

Baseline characteristics and survival of patients of idiopathic pulmonary fibrosis: a longitudinal analysis of the Swedish IPF Registry.

BACKGROUND: Observational data under real-life conditions in idiopathic pulmonary fibrosis (IPF) is scarce. We explored anti-fibrotic treatment, disease severity and phenotypes in patients with IPF from the Swedish IPF Registry (SIPFR). METHODS: Patients enrolled between September 2014 and April 2020 and followed ≥ 6 months were investigated. Demographics, comorbidities, lung function, composite variables, six-minute walking test (6MWT), quality of life, and anti-fibrotic therapy were evaluated. Agreements between classification of mild physiological impairment (defined as gender-age-physiology (GAP) stage 1) with physiological and composite measures of severity was assessed using kappa values and their impact on mortality with hazard ratios. The factor analysis and the two-step cluster analysis were used to identify phenotypes. Univariate and multivariable survival analyses were performed between variables or groups. RESULTS: Among 662 patients with baseline data (median age 72.7 years, 74.0% males), 480 had a follow up ≥ 6 months with a 5 year survival rate of 48%. Lung function, 6MWT, age, and BMI were predictors of survival. Patients who received anti-fibrotic treatment ≥ 6 months had better survival compared to untreated patients [p = 0.007, HR (95% CI): 1.797 (1.173-2.753)] after adjustment of age, gender, BMI, smoking status, forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO). Patients with mild physiological impairment (GAP stage 1, composite physiological index (CPI) ≤ 45, DLCO ≥ 55%, FVC ≥ 75%, and total lung capacity (TLC) ≥ 65%, respectively) had better survival, after adjustment for age, gender, BMI and smoking status and treatment. Patients in cluster 1 had the worst survival and consisted mainly of male patients with moderate-severe disease and an increased prevalence of heart diseases at baseline; Cluster 2 was characterized by mild disease with more than 50% females and few comorbidities, and had the best survival; Cluster 3 were younger, with moderate-severe disease and had few comorbidities. CONCLUSION: Disease severity, phenotypes, and anti-fibrotic treatment are closely associated with the outcome in IPF, with treated patients surviving longer. Phenotypes may contribute to predicting outcomes of patients with IPF and suggest the patients' need for special management, whereas single or composite variables have some limitations as disease predictors.

The ratio FEV1 /FVC and its association to respiratory symptoms-A Swedish general population study.

Chronic airflow limitation (CAL) can be defined as fixed ratio of forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC) < 0.70 after bronchodilation. It is unclear which is the most optimal ratio in relation to respiratory morbidity. The aim was to investigate to what extent different ratios of FEV1 /FVC were associated with any respiratory symptom. In a cross-sectional general population study, 15,128 adults (50-64 years of age), 7,120 never-smokers and 8,008 ever-smokers completed a respiratory questionnaire and performed FEV1 and FVC after bronchodilation. We calculated different ratios of FEV1 /FVC from 0.40 to 1.0 using 0.70 as reference category. We analysed odds ratios (OR) between different ratios and any respiratory symptom using adjusted multivariable logistic regression. Among all subjects, regardless of smoking habits, the lowest odds for any respiratory symptom was at FEV1 /FVC = 0.82, OR 0.48 (95% CI 0.41-0.56). Among never-smokers, the lowest odds for any respiratory symptom was at FEV1 /FVC = 0.81, OR 0.53 (95% CI 0.41-0.70). Among ever-smokers, the odds for any respiratory symptom was lowest at FEV1 /FVC = 0.81, OR 0.43 (95% CI 0.16-1.19), although the rate of inclining in odds was small in the upper part, that is FEV1 /FVC = 0.85 showed similar odds, OR 0.45 (95% CI 0.38-0.55). We concluded that the odds for any respiratory symptoms continuously decreased with higher FEV1 /FVC ratios and reached a minimum around 0.80-0.85, with similar results among never-smokers. These results indicate that the optimal threshold associated with respiratory symptoms may be higher than 0.70 and this should be further investigated in prospective longitudinal studies.

MicroRNA miR-24-3p reduces DNA damage responses, apoptosis, and susceptibility to chronic obstructive pulmonary disease.

The pathogenesis of chronic obstructive pulmonary disease (COPD) involves aberrant responses to cellular stress caused by chronic cigarette smoke (CS) exposure. However, not all smokers develop COPD and the critical mechanisms that regulate cellular stress responses to increase COPD susceptibility are not understood. Because microRNAs are well-known regulators of cellular stress responses, we evaluated microRNA expression arrays performed on distal parenchymal lung tissue samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA that best correlated with radiographic emphysema and validated this finding in multiple cohorts. In a CS exposure mouse model, inhibition of miR-24-3p increased susceptibility to apoptosis, including alveolar type II epithelial cell apoptosis, and emphysema severity. In lung epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue, and BIM and BRCA1 expression inversely correlated with miR-24-3p. We concluded that miR-24-3p, a regulator of the cellular response to DNA damage, is decreased in COPD, and decreased miR-24-3p increases susceptibility to emphysema through increased BIM and apoptosis.

Chronic airflow limitation and its relation to respiratory symptoms among ever-smokers and never-smokers: a cross-sectional study.

BACKGROUND: The diagnosis of chronic obstructive pulmonary disease is based on the presence of persistent respiratory symptoms and chronic airflow limitation (CAL). CAL is based on the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1:FVC) after bronchodilation, and FEV1:FVC less than the fifth percentile is often used as a cut-off for CAL. The aim was to investigate if increasing percentiles of FEV1:FVC were associated with any respiratory symptom (cough with phlegm, dyspnoea or wheezing) in a general population sample of never-smokers and ever-smokers. METHODS: In a cross-sectional study comprising 15 128 adults (50-64 years), 7120 never-smokers and 8008 ever-smokers completed a respiratory questionnaire and performed FEV1 and FVC after bronchodilation. We calculated their z-scores for FEV1:FVC and defined the fifth percentile using the Global Lung Function Initiative (GLI) reference value, GLI5 and increasing percentiles up to GLI25. We analysed the associations between different strata of percentiles and prevalence of any respiratory symptom using multivariable logistic regression for estimation of OR. RESULTS: Among all subjects, regardless of smoking habits, the odds of any respiratory symptom were elevated up to the GLI15-20 strata. Among never-smokers, the odds of any respiratory symptom were elevated at GLI<5 (OR 3.57, 95% CI 2.43 to 5.23) and at GLI5-10 (OR 2.57, 95% CI 1.69 to 3.91), but not at higher percentiles. Among ever-smokers, the odds of any respiratory symptom were elevated from GLI<5 (OR 4.64, 95% CI 3.79 to 5.68) up to GLI≥25 (OR 1.33, 95% CI 1.00 to 1.75). CONCLUSIONS: The association between percentages of FEV1:FVC and respiratory symptoms differed depending on smoking history. Our results support a higher percentile cut-off for FEV1:FVC for never-smokers and, in particular, for ever-smokers.

Minimal Clinically Important Differences and Feasibility of Dyspnea-12 and the Multidimensional Dyspnea Profile in Cardiorespiratory Disease.

CONTEXT: Breathlessness is a cardinal symptom in cardiorespiratory disease and consists of multiple dimensions that can be measured using the instruments Dyspnea-12 (D12) and the Multidimensional Dyspnea Profile (MDP). OBJECTIVES: The objective of the study is to determine the minimal clinically important differences (MCIDs) of all D12 and MDP summary and subdomain scores as well as the instruments' feasibility in patients with cardiorespiratory disease. METHODS: Prospective multicenter cohort study of outpatients with diagnosed cardiorespiratory disease and breathlessness in daily life. D12 and MDP were assessed at baseline, after 30-90 minutes and two weeks. MCIDs were calculated using anchor-based and distributional methods for summary and subdomain scores. Feasibility was assessed as rate of missing data, help required, self-reported difficulty, and completion time. RESULTS: A total 182 outpatients (53.3% women) were included; main diagnoses were chronic obstructive pulmonary disease (COPD; 25%), asthma (21%), heart failure (19%), and idiopathic pulmonary fibrosis (19%). Anchor-based MCIDs were for D12 total score 2.83 (95% CI 1.99-3.66); D12 physical 1.81 (1.29-2.34); D12 affective 1.07 (0.64-1.49); MDP A1 unpleasantness 0.82 (0.56-1.08); MDP perception 4.63 (3.21-6.05), and MDP emotional score 2.37 (1.10-3.64). The estimates were consistent with small-to-moderate effect sizes using distributional analysis, and MCIDs were similar between COPD and non-COPD patients. The instruments were generally feasible and quick to use. CONCLUSION: D12 and MDP are responsive to change and feasible for use for assessing multidimensional breathlessness in outpatients with cardiorespiratory disease. MCIDs were determined for use as endpoints in clinical trials.

Assessment of Global Lung Function Initiative (GLI) reference equations for diffusing capacity in relation to respiratory burden in the Swedish CArdioPulmonary bioImage Study (SCAPIS).

The Global Lung Function Initiative (GLI) has recently published international reference values for diffusing capacity of the lung for carbon monoxide (D LCO). Lower limit of normal (LLN), i.e. the 5th percentile, usually defines impaired D LCO We examined if the GLI LLN for D LCO differs from the LLN in a Swedish population of healthy, never-smoking individuals and how any such differences affect identification of subjects with respiratory burden.Spirometry, D LCO, chest high-resolution computed tomography (HRCT) and questionnaires were obtained from the first 15 040 participants, aged 50-64 years, of the Swedish CArdioPulmonary bioImage Study (SCAPIS). Both GLI reference values and the lambda-mu-sigma (LMS) method were used to define the LLN in asymptomatic never-smokers without respiratory disease (n=4903, of which 2329 were women).Both the median and LLN for D LCO from SCAPIS were above the median and LLN from the GLI (p<0.05). The prevalence of D LCO GLI LLN but GLI LLN but GLI LLN and >SCAPIS LLN). No differences were found with regard to physician-diagnosed asthma.The GLI LLN for D LCO is lower than the estimated LLN in healthy, never-smoking, middle-aged Swedish adults. Individuals with D LCO above the GLI LLN but below the SCAPIS LLN had, to a larger extent, an increased respiratory burden. This suggests clinical implications for choosing an adequate LLN for studied populations.

Secretory anti-citrullinated protein antibodies in serum associate with lung involvement in early rheumatoid arthritis.

OBJECTIVE: A 'mucosal connection' in RA presently attracts increasing attention. We recently described the occurrence of secretory antibodies to citrullinated protein (SC-ACPA) in sera from patients with recent-onset RA. The current study was performed to evaluate possible associations between serum levels of secretory ACPA and signs of lung involvement in patients with early, untreated RA. METHODS: One hundred and forty-two RA patients were included as part of the 'LUng Investigation in newly diagnosed RA' study. One hundred and six patients were examined with high-resolution CT (HRCT) and 20 patients underwent bronchoscopy, where bronchial biopsies and bronchoalveolar lavage fluid (BALF) samples were obtained. SC-ACPA in serum and BALF were detected by an enzyme-linked immunoassay. Antibody levels were related to smoking history, pulmonary function, HRCT, BALF cell counts and findings in bronchial biopsies. RESULTS: SC-ACPA occurred in 16% of the serum samples and in 35% of the BALF samples. SC-ACPA levels in serum correlated with SC-ACPA levels in BALF (σ = 0.50, P = 0.027) and were higher among patients with HRCT parenchymal lung abnormalities (P = 0.022) or bronchiectasis (P = 0.042). Also, ever smoking was more frequent among serum SC-ACPA-positive patients (91% vs 67%, P = 0.023), and the SC-ACPA levels correlated with the number of pack-years (σ=0.20, P = 0.020). CONCLUSION: In early, untreated RA, serum levels of SC-ACPA reflect lung involvement in terms of local ACPA levels, smoking and lung abnormalities on HRCT. These findings strengthen the link between mucosal ACPA responses and the lungs in RA.

Gender differences at presentation of idiopathic pulmonary fibrosis in Sweden.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease with poor prognosis mainly affecting males. Differences in clinical presentation between genders may be important both for the diagnostic work-up and for follow-up. In the present study, we therefore explored potential gender differences at presentation in a Swedish cohort of IPF-patients. METHODS: We studied patients included in the Swedish IPF- registry over a three-year period from its launch in 2014. A cross-sectional analysis was performed for data concerning demographics, lung function, 6- min walking test (6MWT) and quality of life (QoL) (King's Brief Interstitial Lung Disease (K-BILD) score). RESULTS: Three hundred forty- eight patients (250 (72%) males, 98 (28%) females, median age 72 years in both genders) were included in the registry during the study period. Smoking history (N = 169 (68%) vs. N = 53 (54%), p < 0.05), baseline lung function (Forced vital capacity, % of predicted (FVC%): 68.9% ± 14.4 vs. 73.0% ± 17.7, p < 0.05; Total lung capacity, % of predicted (TLC%): 62.2% ± 11.8 vs. 68.6% ± 11.3%, p < 0.001) were significantly different at presentation between males and females, respectively. Comorbidities such as coronary artery disease (OR: 3.5-95% CI: 1.6-7.6) and other cardiovascular diseases (including atrial fibrillation and heart failure) (OR: 3.8-95% CI: 1.9-7.8) also showed significant differences between the genders. The K- BILD showed poor quality of life, but no difference was found between genders in total score (54 ± 11 vs. 54 ± 10, p = 0.61 in males vs. females, respectively). CONCLUSIONS: This study shows that female patients with IPF have a more preserved lung function than males at inclusion, while males have a significant burden of cardiovascular comorbidities. However, QoL and results on the 6MWT did not differ between the groups. These gender differences may be of importance both at diagnosis and follow- up of patients with IPF.

Dysregulation of the Tryptophan Pathway Evidences Gender Differences in COPD.

Increased activity of indoleamine 2,3-dioxygenase (IDO) and tryptophan hydroxylase (TPH) have been reported in individuals with chronic obstructive pulmonary disease (COPD). We therefore investigated the effect of gender stratification upon the observed levels of tryptophan metabolites in COPD. Tryptophan, serotonin, kynurenine, and kynurenic acid were quantified in serum of never-smokers (n = 39), smokers (n = 40), COPD smokers (n = 27), and COPD ex-smokers (n = 11) by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The individual metabolite associations with lung function, blood, and bronchoalveolar lavage (BAL) immune-cell composition, as well as chemokine and cytokine levels, were investigated. Stratification by gender and smoking status revealed that the observed alterations in kynurenine and kynurenic acid, and to a lesser extent serotonin, were prominent in males, irrespective of COPD status (kynurenine p = 0.005, kynurenic acid p = 0.009, and serotonin p = 0.02). Inferred serum IDO activity and kynurenine levels decreased in smokers relative to never-smokers (p = 0.005 and p = 0.004, respectively). In contrast, inferred tryptophan hydroxylase (TPH) activity and serotonin levels showed an increase with smoking that reached significance with COPD (p = 0.01 and p = 0.01, respectively). Serum IDO activity correlated with blood CXC chemokine ligand 9 (CXCL9, p = 0.0009, r = 0.93) and chemokine (C-C motif) ligand 4 (CCL4.(p = 0.04, r = 0.73) in female COPD smokers. Conversely, serum serotonin levels correlated with BAL CD4+ T-cells (%) (p = 0.001, r = 0.92) and CD8+ T-cells (%) (p = 0.002, r = -0.90) in female COPD smokers, but not in male COPD smokers (p = 0.1, r = 0.46 and p = 0.1, r = -0.50, respectively). IDO- and TPH-mediated tryptophan metabolites showed gender-based associations in COPD, which were primarily driven by smoking status.

Patient journey and treatment patterns in adults with IPF based on health care data in Sweden from 2001 to 2015.

BACKGROUND: For patients with idiopathic pulmonary fibrosis (IPF), there is limited real-world data on patient journey and treatment patterns. AIM: To explore predictors of early diagnosis and treatment initiation, and treatment patterns in IPF patients using linked data from Swedish registers and electronic medical records (EMRs). POPULATION: A national cohort (C1) of 17,247 pulmonary fibrosis patients (ICD-10 code J84.1; no competing diagnosis) diagnosed between 2001 and 2015, and an EMR-based regional subset (C2) comprising 1755 IPF patients diagnosed between 2004 and 2017. The time from early disease symptoms to diagnosis, use of anti-fibrotic medications, time from diagnosis to initiation of anti-fibrotic treatment, and adherence, persistence and treatment length with pirfenidone were explored in these patients. RESULTS: In C1, the median time to diagnosis from the first symptoms dyspnoea, cough and fatigue were 307, 563 and 639 days, respectively. Glucocorticoids were the most frequently prescribed medication. Less than 10% of patients undergoing or initiating treatment, used pirfenidone or nintedanib. Males had a higher probability of initiating anti-fibrotic treatment than females within a year of diagnosis. One-year persistence in pirfenidone patients was 42% in C1 and 25% in C2. CONCLUSION: Diagnosis of pulmonary fibrosis was delayed in patients with cough and fatigue, which are early symptoms of IPF. This, and lower than expected utilisation of anti-fibrotic medications, suggests missed opportunities for early disease diagnosis and treatment. The high rate of treatment discontinuation underscores the importance of supporting and guiding patients to persist with their medications to ensure an accrual benefit of treatment.